Gene targeting in embryonic stem (ES) cells is being used to inactivate (knock-out) genes and use the mutated ES cells to generate mice with a mutation at the targeted locus. The cystatin C gene has been cloned and used to make gene targeting constructs. Cystatin-C knock-out mice have been made. These mice do not produce any mouse Cystatin C RNA or protein. They breed normally, but are less aggressive than normal mice and have reduced horizontal movement activity. Further pathological and neurological evaluation is in progress. Human mutant Cystatin C knock-in mice are also being developed in order to make an animal model for hereditary stroke. The knock-in is done with a mutant Cystatin C gene from a patient with hereditary cerebral angiopathy.